Circuit Mechanisms for Auditory Processing in the Inferior Colliculus

下丘听觉处理的电路机制

• 批准号: 10407488
• 负责人: Michael Thomas Roberts
• 金额: $ 43.7万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-10 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10407488
• 关键词: Anatomy; Auditory; Auditory Prosthesis; Auditory system; Axon; Brain; Brain Stem; Brain region; Cell Nucleus; Code; Complex; Data; Dendrites; Electrophysiology (science); Excitatory Synapse; Exhibits; Family; Frequencies; Glutamates; Hearing; Inferior Colliculus; Inhibitory Synapse; Intervention; Investigation; Knowledge; Label; Maps; Measures; Midbrain structure; Molecular; Morphology; Neurons; Neurophysiology - biologic function; Noise; Outcomes Research; Output; Pattern; Physiological; Physiology; Play; Population; Process; Property; Research; Role; Sampling; Slice; Sound Localization; Source; Speech; Stimulus; Synapses; Synaptic Transmission; Testing; Time; Training Activity; Vasoactive Intestinal Peptide; Viral; auditory processing; auditory thalamus; base; evidence base; excitatory neuron; experimental study; falls; hearing impairment; improved; in vivo; inhibitory neuron; insight; molecular marker; neural circuit; neuropeptide Y; novel; optogenetics; postsynaptic; postsynaptic neurons; receptive field; response; sound; sound frequency; speech in noise; speech recognition; stellate cell; superior colliculus Corpora quadrigemina; tool; vocalization

Abstract The inferior colliculus (IC) is the midbrain hub of the central auditory system. Although the IC is a critical processing center for speech, vocalizations, and other complex sounds, the neuronal mechanisms underlying computations in the IC remain largely unknown. This gap in knowledge persists because it has proven difficult to reliably identify specific classes of IC neurons. By combining molecular markers with anatomical and physiological measures, we recently overcame this obstacle and have identified two novel classes of IC principal neurons: vasoactive intestinal peptide (VIP) neurons and neuropeptide Y (NPY) neurons. VIP neurons are excitatory, glutamatergic neurons, while NPY neurons are inhibitory, GABAergic neurons. Both VIP and NPY neurons are stellate neurons with dendritic arbors that spread across the tonotopic axis of the central nucleus of the IC (ICc), and both project to multiple brain regions, including the auditory thalamus. Because they can sample input from a range of sound frequencies, it has long been hypothesized that ICc stellate neurons play important roles in sound processing, but the functional roles of stellate neurons have previously been inaccessible. By identifying VIP and NPY neurons, we possess the tools for the first time to selectively target and manipulate an excitatory and an inhibitory class of ICc stellate neurons. The overall objective of this proposal is to establish a functional wiring diagram for the inputs and outputs of VIP and NPY neurons and to determine the differences in how VIP and NPY neurons respond to sounds. To pursue this objective, we will use viral tract tracing, optogenetic circuit mapping, brain slice electrophysiology, and optogenetically-targeted in vivo recordings. In Aim 1, we will identify the ascending sources of auditory input to VIP and NPY neurons and determine how these inputs vary their synaptic strength during trains of activity. In Aim 2, we will identify the long-range targets and terminal arborization patterns of VIP and NPY neurons and determine how synaptic transmission from VIP and NPY neurons influences neurons in the auditory thalamus. In Aim 3, we will test the hypothesis that excitatory VIP neurons and inhibitory NPY neurons differ in their responses to tones and noise and to amplitude- and frequency-modulated sounds, stimuli that represent important features of speech and other vocalizations. The expected outcome of this research is that we will determine for the first time how two classes of ICc stellate neurons, one excitatory and one inhibitory, integrate ascending and descending auditory input, influence long-range postsynaptic targets, and respond to simple and complex sounds. These results will generate evidence-based hypotheses about how ICc stellate neurons contribute to sound processing and will provide a launching point for investigations into the circuit computations that underlie speech and vocalization coding in the midbrain.

摘要 下丘是中枢听觉系统的中脑中枢。尽管IC是一个关键的 语音、发声和其他复杂声音的处理中心，潜在的神经机制 集成电路中的计算在很大程度上仍然是未知的。这种知识差距之所以持续存在，是因为事实证明它很难 以可靠地识别特定类别的IC神经元。通过将分子标记与解剖学和 生理测量，我们最近克服了这一障碍，并发现了两类新的IC 主要神经元：血管活性肠肽(VIP)神经元和神经肽Y(NPY)神经元。血管活性肠肽神经元 NPY神经元是兴奋性的谷氨酸能神经元，而NPY神经元是抑制性的GABA能神经元。贵宾和 NPY神经元是具有树突的星状神经元，分布在中枢的紧张轴上。 IC核(ICC)，两者都投射到多个大脑区域，包括听觉丘脑。因为 他们可以从一系列声音频率中采样输入，长期以来一直假设ICC是星形的 神经元在声音处理中扮演着重要的角色，而星状神经元的功能角色之前 一直无法接近。通过识别VIP和NPY神经元，我们第一次拥有了选择性地 靶向和操控一类兴奋性和抑制性ICC星状神经元。这样做的总体目标是 建议为VIP和NPY神经元的输入和输出建立功能接线图，并 确定VIP和NPY神经元对声音反应的差异。为达致这个目标，我们会 使用病毒道追踪、光基因线路标测、脑片电生理学和光基因靶向 活体录像。在目标1中，我们将确定VIP和NPY神经元的听觉输入的上升来源 并确定这些输入在一系列活动过程中如何改变它们的突触强度。在目标2中，我们将确定 VIP和NPY神经元的远程靶点和终末分支模式及其决定突触方式的研究 VIP和NPY神经元的传递影响听觉丘脑的神经元。在目标3中，我们将测试 兴奋性VIP神经元和抑制性NPY神经元对音调和噪声反应不同的假说 以及调幅和调频的声音、代表语音和 其他发音。这项研究的预期结果是，我们将首次确定两个 一类兴奋性和一类抑制性ICC星状神经元整合了上行和下行听觉 输入，影响远距离突触后目标，并对简单和复杂的声音做出反应。这些结果将 生成基于证据的假设，说明ICC星状神经元如何促进声音处理 为研究作为语音和发声基础的电路计算提供了起点 在中脑进行编码。